Bicycloheptene and bicyclooctene-2-carboxylic acid esters



Patented Aug. 31, 1954 TATS FFICE BICYCLOHEPTENE AND BICYCLOOGTENE-Z-CARBOXYLIC ACID ESTERS tion of Illinois No Drawing. Application April29, 1953, Serial No. 352,041

12 Claims. 1

The present application is a continuation-inpart of my copendingapplication, Serial Number 249,005, filed September 29, 1951, nowforfeited. It relates to a new group of basic esters of polycarbocyclicacids and, particularly, to the basic esters ofbicyclo[2.2.l]--heptene-2-carboxylic acid and bicyclo[2.2.2] 5octene-Z-carboxylic acid, their salts, and the nuclearly alkylatedsubstituents thereof. While this alkyl substitution may be at any of thenuclear carbon atoms, the 2- and 3- positions are preferred for thepurposes of the present invention. The compounds with which thisinvention is particularly concerned are those of the general structuralformula shown and their salts, wherein n is one or two, X, Y, and Z areeither hydrogen or lower alkyl radicals, A is a bivalent aliphatichydrocarbon radical containing at least 2 carbon atoms and NR'R is alower alkylamino radical, dialkyl amino radical or a nitrogen-containingheterocyclic radical attached through a nitrogen in the heterocycle tothe radical A.

In the foregoing structural formula the radicals X, Y, alkyl radicals asmethyl, ethyl, and straightchained and branch-chained propyl, butyl,amyl, and hexyl.

The radical A is derived from such straight or branch-chained aliphatichydrocarbon radicals as ethylene, propylene, butylene, amylene, hexyleneor polymethylene radicals such as trimethylene, tetramethylene,pentamethylene and hexamethylene.

The radicals R, and R" can be lower alkyl groups. The radical NRR" canalso be a nitrogen-containing lower heterocycle such as piperazine,N'-alkylpiperazine, thiamorpholine, quincand Z can be hydrogen or suchlower line, and isoquinoline, but of particular interest are theheterocyclic radicals of the type as in the case of pyrrolidine,piperidino, 2,5-dimethylpyrrolidino and 2,6-lupetidino radicals.

The organic bases described herein form salts non-toxic in therapeuticdosage with a variety of inorganic and strong organic acids, includingsulfuric, phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic,citric, lactic, maleic, malic, succinic, tartaric, cinnamic, acetic,benzoic, gluconic, ascorbic, and related acids. They also formquaternary ammonium salts with a variety of organic esters of sulfuric,hydrohalic and aromatic sulfonic acids. Among such esters are methylchloride, bromide and iodide; ethyl chloride, propyl chloride, butylbromide, isobutyl chloride, benzyl chloride, phenethyl chloride,naphthylmethyl chloride, dimethyl sulfate, methyl benzenesulfonate,ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin,allyl chloride, methallyl bromide and crotyl bromide.

The acids which constitute the starting materials for the invention areprepared by a Diels- Alder addition of a compound of the type OX 11/ owherein D is a hydrogen or lower alkyl group, and X, Y, and Z aredefined as hereinabove, to cyclopentadiene and cyclohexadiene, as shownby Alder et al., Annalen der Chemie, vol. 514, pages 197 et seq. 1934,Fiesselmann, Berichte deut. chem. Ges., vol. 75, pages 881 et seq., 1942and Seka et al., ibid, pages 1379 et seq. Esterification is carried outin the conventional manner.

The esters which constitute the present invention are valuable asintermediates in organic synthesis. Thus organic azides can be caused toadd across the 5,6-double bond to form compounds of the type wherein Ris an alkyl or aryl radical.

The claimed compounds are of special value as medicinal agents becauseof their action on blood pressure and their diuretic efiect. Thequaternary salts are of special interest because of their inhibitoryeffect on the transmissionof nerve impulses in the autonomic nervoussystem. Certain 3 of the quaternary ammonium salts are activeingredients in parasiticidal compositions of matter. It has also beenfound that the claimed compounds cause release of adrenocorticotrophichormone from the pituitary gland.

My invention is disclosed in further detail by the following exampleswhich are set forth for the purpose of illustrating this invention, butare in no way to be construed as limiting it in spirit or in scope. Itwill be apparent to those skilled in the art that many modifications inmethods, conditions and materials can be adopted without departingtherefrom. In these examples temperatures are given uncorrected indegrees centigrade C.), pressures during vacuum distillation inmillimeters (mm) of mercury, and quantities of materials in parts byweight.

EXAMPLE 1 fl-Diethylaminoethyl ester of bicycZo[2.2.1l-5-heptene-Z-carboarylic acid A mixture of 270 parts of bicyclo[2.2.1]-5-heptene-Z-carboxylic acid and 280 parts of B- chloroethyl-diethylaminein 800 parts of 2-propanol is heated at reflux temperature with stirringfor 8 hours. A precipitate forms within a short time. After completionof the reaction, this precipitate is collected on a filter and themother liquor concentrated to give an additional precipitate. The solidresidues are combined, dissolved in water, washed with ether, renderedalkaline and extracted with ether. The ether extract is dried overanhydrous calcium sulfate, filtered and evaporated. The residue containsthe B-diethylaminoethyl ester of bicyclo[2.2.l] 5-heptene-2-carboxylicacid which is distilled at about 94-96 C. and 0.2 mm. pressure.

119 parts of this base are dissolved in 3000 parts of anhydrous etherand treated with one equivalent of a 25% solution of hydrogen chloridein anhydrous ethanol. There is an immediate formation of a whiteprecipitate. Recrystallized from anhydrous ethyl acetate thehydrochloride melts at about l3'7l38 C.

EXAMPLE 2Bicyclo[2.2.1]-5-heptene-2-carboaryethyld-iethylmethyl-ammonium bromideA mixture of 136 parts of the B-diethylaminoethyl ester ofbicyclol2.2.1] 5 heptene 2 carboxylic acid and 95 parts of methylbromide in 240 parts of butanone is sealed in a pressure reactor and,after standing for several days at room temperature, poured into 3000parts of anhydrous ether. The bicyclo [2.2.1-5-heptene-2-carboxyethyldiethylmethylammonium bromide crystallizes andis collected on a filter and dried. The hygroscopic crystals melt atabout 100-102 C.

The compound has the structural formula 011 cm ll 0H1 02115 (,H\ [/03C2115 CH COO-CH2 CH2N EXAMPLE 3 p-Dimcthylaminoethyl ester ofbicycZo[2.2.2]--

octene-2carb0:cylic acid A mixture of 500 parts of freshly distilledcyclohexadiene, 800 parts of methyl acrylate and 4 a small amount ofhydroquinone are placed into a bomb and heated at 160-170 for 12 hours.After cooling the contents are removed with ether and the resultingsolution is refluxed for 10 hours with a solution of 825 parts ofpotassium hydroxide in 330 parts of water and 2400 parts of methanol.The solvent is stripped under vacuum and the residue is dissolved inwater, washed with ether, made acidic with dilute hydrochloric acid andextracted with ether. The extract is washed with water, dried overanhydrous calcium chloride, filtered and evaporated to yield thebicyclo- [2.2.21-5-octene-2-carboxylic acid which is distilled at aboutIDS-112 C. and 0.2 mm. pressure.

A mixture of 325 parts of this acid, 297 parts of thionyl chloride and 2parts of pyridine in 1700 parts of benzene is refluxed for minutes,cooled and filtered with filter aid. The filtrate containing thebicyclo-[2.2.2l-5-octene-2-carbonyl chloride is diluted with 2700 partsof henzene and mixed with 288 parts of B-dimethylaminoethanol. Afterrefluxing for 3.5 hours the solvent is removed under vacuum and theresidue is dissolved in Water, washed with ether, made alkaline andextracted with ether. This extract is washed with Water, dried overanhydrous calcium sulfate, filtered and evaporated to yield thefl-dimethylaminoethyl ester of bicyclo-[2.2.2l-5- octene-Z-carboxylicacid which is distilled at about 89-91 C. and 0.3 mm. pressure.

An ether solution of this base is treated with one equivalent of a 25%solution of hydrogen chloride in absolute Z-propanol. A copious whiteprecipitate forms at once. The latter is collected on a filter andrecrystallized from absolute ethyl acetate by addition of a small amountof 2- propanol. The hydrochloride melts at about 163-165 C.

EXAMPLE 4 Bicycle [2.2.2] -5octene-2-carboa:yethyltrimcthylammoniumbromide J1 CH: l

H1 0 I CHCOOCHzCH2-N(CH:);

OH Br EXAMPLE 5 p-Pyrrolidinoethyl ester of bicyclo[2.2.2l -5-octene-Z-carboxylic acid A benzene solution of bicyclo[2.2.2l-5-octene-Z-carbonyl chloride, obtained as in Example 3 from 325 parts of theacid, is mixed with 372 parts of N-(B-hydroxyethyl)-pyrrolidine and,after subsidence of the initial exothermic reaction, the mixture isrefluxed for 4 hours and then concentrated under vacuum. The residue isdissolved in water, washed with ether, treated with sodium hydroxide toalkalinity and then extracted with ether. This ether extract is washedEXAMPLE 6 p-Diethylaminoethyl ester of Z-methyZ-bicyclo- [2.2.1]-5-heptene-2-carboa:ylic acid A mixture of 200 parts ofZ-methyI-bicyclo- [2.2.1]-5-heptene-2-carboxylic acid and 180 parts of,6-chloroethy1diethylamine in 800 parts of 2- propanol is heated atreflux temperature with stirring for 7 hours. The solvent is partiallyremoved by evaporation and the precipitate dissolved in water. Afterwashing with ether the aqueous solution is rendered. alkaline byaddition of sodium hydroxide and extracted with ether. The ether extractis dried over anhydrous potassium carbonate, filtered and evaporated.The residue of B-diethylaminoethyl ester ofZ-methylbicyclo[2.2.l]-5-heptene-2-carboxylic acid is distilled at about105-109 C. and. 1.5 mm. pressure.

'70 parts of the base are dissolved in 3500 parts of anhydrous ether andtreated with one equivalent of absolute alcoholic hydrogen chloride. Theimmediately forming white precipitate is recrystallized from anhydrousethyl'acetate. The hydrochloride thus obtained melts at about 135- 137C.

EXAMPLE '7 2-methyZ-bicycZo[2.2.1]-5-heptene-2carboryethyZdiethylmethylammonium bromide on cH, I' OH: CH31 H o EXAMPLE 8 "y- (N -morpholino) propyl ester of Z-ethyl-bicyclo-[2.2.1] -5-heptene-2-carboxylic acid A mixture of 100 parts of2-ethyl-bicyclo- [2.2.1]-5-heptene-2-carboxy1ic acid and. 100 parts ofN-(y-chloropropyl) morpholine in 400 parts of absolute 2-propanol isheated at reflux temperature for 10 hours with mechanical stirring. Thesolvent is stripped 011 and the solid precipitate dissolved in water.The aqueous solution is washed with ether, rendered alkaline by theaddi- 6 tion of dilute sodium hydroxide and extracted with ether. Theether extract is dried over an: hydrouscalcium sulfate, stirred withdecolorizing 'charcoal, filtered and evaporated. There remains the*y-(N-morpholinwpropyl ester of 2- ethyl-bicyclo [2.2.1]-5-heptene-2-carboxylic acid as a clear yellow oil which has thestructural formula I EXAMPLE 9 ;3Diethylaminoethyl ester of3-methyl-bicyclo- [2.2.1] -5-heptene-2-carboxylic acid TheB-diethylaminoethyl ester ofB-methyl-bicyclo[2.2.1.l-5-heptene-2-carboxylic acid is obtained as anoil which distills at about -106 C. and 1-1.2 mm. pressure.

A solution of 100 parts of this base in 3000 parts of anhydrous ether istreated with one equivalent of a solution of hydrogen chloride inabsolute alcohol. The immediately forming white precipitate isrecrystallized from anhydrous ethyl acetate. The hydrochloride melts atabout 118.5-119.5 C.

EXAMPILE 10 3-methyZ-bicyclo[2.2.1]-5-heptene-2-carbo:vyethyldiethylmethylammonium bromide tained as ahygroscopic material melting at about 98-l00 C. Treatment of a solutionof 3 mols of the bromide in Z-propanol with 1 mol of silver citrate and2 mols of citric acid by stirring at room temperature, removal of theprecipitated silver bromide by filtration and concentration of thefiltrate yields the dihydrogen citrate. The cation has the structuralformula 7 EXAMPLEII y-Diisopropylaminopropyl ester of3-ethyl=-bicycZo[2.2.1l --heptene-2-carboa:y,lic acid A. mixture of 1'78parts. of v-chloropropyldiiscprcpylamine. and 166; parts ofs-ethylrbicyclo- E2.2.1l-fi -heptene-2-carboxylic acid in- 700- parts ofanhydrous propanol is heated with mechanical stirring at refluxtemperature for hours, concentrated in vacuum and extracted with water.The aqueous extract is washed with ether and rendered alkaline byaddition of dilute sodium hydroxide. The alkaline solution is extractedwith ether and the ether extract dried over anhydrous calcium sulfate,stirred with decolorizing charcoal, filtered and evaporated, yieldingthe 'y diisopropylaminopropyl ester of 3 ethylbicyclol'2.2.1l-5-heptene-2-carboxylic acid as a clear orange oilboiling at about 120-124" C. and

about 0.5 mm. pressure. It has the structural formula EXAMPLE 12fl-(N-Zfi-Zupetidino)ethyl ester of2,3-diethylbicyclo[2.2.1]-5-heptene-2-carbo:rylic acid A mixture of 194parts of 2,3-diethyl-bicyclo- [2.2.1]-5-heptene-2-carboxylic acid and175 parts of N-(B-chloroethyl) -2,6-lupetidine in 1000 parts ofanhydrous. 2-propanol is heated at reflux temperature with mechanicalstirring for 12 hours and then concentrated. The solid precipitate isextracted with water and the aqueous extract washed. with ether andrendered alkaline by the addition of dilute potassium hydroxide. Thebase is. extracted with ether and the ether extract is dried overanhydrous potassium carbonate, stirred with decolorizing charcoal,filtered and evaporated. The resulting B-(N-2,6-lupetidino)- ethyl esterof 2,3-diethyl-bicyclo[2.2.1]-5-hep tene-Z-carboxylic acid is obtainedas. a clear amber oil which has the structural formula EXAMPLE 13t-Dimethylaminobutyl ester of3,3-dimethyZ-bicyclo[2.2.1]-5'-heptene-2-carbomylic acid A mixture of166 parts of 3,3-dimethyl-bicyc1o- [2.2.1 -5-heptene2carboxylic acid and140 parts of e-chlorobutyldimethylamine in800 partsof anhydrous2-propanol is stirred and heated atrefiux temperature for 10 hours,concentrated and extracted with Water. The aqueous solution is washedwith ether, rendered alkaline by addition of sodium carbonate andextracted with ether. The extract is dried over anhydrous potassiumcarbonate, stirred with decolorizing charcoal, filtered and evaporatedto yield the t-dimethylaminobutyl ester of 3,3-dimethyl-bicyclo[2.2.1]-5-heptene-2-carboxylic acid as a clear yellowish 81 oil which boils atabout 104-106 C. and 0.1 mm. pressure. It has the structural formulaEXAMPLE 14 ,8 Ethylaminoethyl. ester of bicyclo[2.2.2l 5octene-Z-carborcylic acid A turbinated mixture. of, 40. parts of thesilver salt of bicyclo[2.2.21-5-octene-2-carboxylic acid and. 40.-parts. of fl-chloroethylethylamine. in 280 parts of anhydrous toluene isheated for 5 hours under reflux. The reaction mixture is filtered andthe filtrate is washed with water and extracted with dilute hydrochloricacid. The, extract is washed with ether, made alkaline by addition ofdilute sodium hydroxide and extracted with ether. This extract is washedwith water, dried over anhydrous calcium sulfate, filtered andevaporated to yield the B-ethylaminoethyl ester of bicyclo[2.2.2l 5octene 2 carboxylic acid which is distilled at about -90 C. and 0.2 mm.pressure.

I claim:

1. A compound of the structural formula wherein n is a positive integersmaller than 3, X, Y, and Z are members of the class consisting ofhydrogen and lower alkyl radicals, A is a lower alkylene radicalseparating the oxygen and nitrogen atoms attached thereto by at leasttwo carbon atoms, and. NR'R" is a member of the class consisting oflower alkylamino radicals, lower dialkylamino radicals, morpholinoradicals and radicals wherein R. and. R" are combined to form a loweralkylene radical containing 4 to '1 carbon atoms.

2. A ell-(lower alkyDaminoalkYl ester ofbicyc1ol2.2..1l-5-heptene-2-carboxylic acid, wherein the nitrogen atomis removed from the carboxyl radical by a lower alkylene radicalcontaining at least two carbon atoms.

3. A compound of the structural formula C H CH2 CH2 (lower alkyl) ll C Ho( c o 0-A-N (lower alkyl);

wherein A is a lower alkylene radical separating the nitrogen atom fromthe carboxyl radical by at least two carbon atoms.

5. A compound of the structural formula CH\ K] CH2 H CH2 CH3 wherein Ais a lower alkylene radical separating the nitrogen atom from thecarboxyl radical by at least two carbon atoms.

6. fl-Diethylaminoethyl ester ofZ-methyl-bicyclo[2.2.l]-5-heptene-2-carboxylic acid.

7. A compound of the structural formula wherein A is a lower alkyleneradical separating the nitrogen atom from the carboxyl radical by atleast two carbon atoms.

8. A compound of the structural formula OH-C o o-A-Naower am n,

H OH-C O O-A-N (lower alkyl):

wherein A is a lower alkylene radical separat ing the nitrogen atom fromthe carboxyl radical by at least two carbon atoms.

9. B-Diethylaminoethyl ester of B-methyl-bicyc1o[2.2.1l-5-heptene-2-carboxylic acid.

10. A compound of the structural formula wherein n is a positive integersmaller than 3, A is a lower alkylene radical separating the oxygen andnitrogen atom attached thereto by at least two carbon atoms, and B is analkylene radical containing 4 to 7 carbon atoms.

No references cited.

1. A COMPOUND OF THE STRUCTURAL FORMULA 